Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3
Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3
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DOI：
10.1182/blood.v97.3.720
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发表时间：
2001-02-01
期刊：
影响因子：
20.3
通讯作者：
Eaves, CJ
中科院分区：
文献类型：
--
作者：
Holyoake, TL;Jiang, XY;Eaves, CJ
以前的研究表明，慢性粒细胞白血病（CML）患者有一个罕见的，但始终可检测到的静止（G（0））白血病（费城染色体阳性和BCR-ABL阳性[BCR-ABL（+）]）CD 34（+）细胞群。在这里描述的研究中，大多数这样的细胞表达原始表型（CD 38（-）、CD 45 RA（-）、CD 71（-）和HLA-DRlo），并且含有生长因子的这些细胞的培养物最终产生比最初循环的CD 34（+）白血病细胞的培养物更大但最初生长更慢的克隆。最初表达BCR-ABL的静止期白血病细胞在不添加生长因子的情况下在单细胞培养物中增殖，从而证明它们能够自发地退出G（0）并进入连续循环状态。有趣的是，在分离时，这些静止期BCR-ABL（+）细胞中很少含有白细胞介素-3（IL-3）或粒细胞集落刺激因子（G-CSF）转录物，而在大多数循环BCR-ABL（+）CD 34（+）细胞中两者都存在。然而，在没有添加生长因子的情况下培养4天后，随着它们进入细胞周期（如Ki-67和cdc 25转录物的上调所示），IL-3转录物变得可检测。这些发现表明白血病的进入在大多数原始白血病细胞群体中，体内（表达BCR-ABL）祖细胞进入静止（G（0））状态的比率最高，与IL-3和G-CSF基因表达的下调相关，并且与IL-3表达的上调相关，自发可逆。这些结果突出了静止CML祖细胞的潜在生理相关性，甚至在治疗的患者中，当细胞因子浓度低时，这些细胞将被预测比它们的静止的正常对应物具有增殖优势。(C)2001年，美国血液学会。
It was previously shown that patients with chronic myeloid leukemia (CML) have a rare but consistently detectable population of quiescent (G(0)) leukemic (Philadelphia chromosome-positive and BCR-ABL-positive [BCR-ABL(+)]) CD34(+) cells. In the study described here, most such cells expressed a primitive phenotype (CD38(-), CD45RA(-), CD71(-), and HLA-DRlo) and cultures of these cells containing growth factors produced ultimately larger, but initially more slowly growing clones than do cultures of initially cycling CD34(+) leukemic cells. Initially quiescent leukemic cells expressing BCR-ABL proliferated in single-cell cultures in the absence of added growth factors, thereby demonstrating their ability to spontaneously exit G(0) and enter a continuously cycling state, Interestingly, on isolation, few of these quiescent BCR-ABL(+) cells contained either interleukin-3 (IL-3) or granulocyte colony-stimulating factor (G-CSF) transcripts, whereas both were present in most cycling BCR-ABL(+) CD34(+) cells. However, after 4 days of culture in the absence of added growth factors and in association with their entry into the cell cycle (as indicated by up-regulation of Ki-67 and cdc25 transcripts), IL-3 transcripts became detectable. These findings show that entry of leukemic (BCR-ABL-expressing) progenitors into a quiescent (G(0)) state in vivo is highest among the most primitive leukemic cell populations, associated with a down-regulation of IL-3 and G-CSF gene expression, and spontaneously reversible in association with up-regulation of IL-3 expression, These results highlight the potential physiologic relevance of quiescent CML progenitors, even in treated patients, In whom these cells would be predicted to have a proliferative advantage over their quiescent normal counterparts when cytokine concentrations are low. (C) 2001 by The American Society of Hematology.